DESCRIPTION (Applicant's Abstract): Tobacco smoking is certainly the most widely spread form of drug addiction. Smoking tobacco is addictive and, if withdrawal syndrome induced by tobacco is less dramatic than the one induced by opiates, it is nevertheless a major factor for the persistence of the addiction. Nicotine has been shown to be the active neuropharmacological agent in tobacco. Previous studies have shown that all addictive drugs, such as cocaine, amphetamine, morphine and nicotine interact with the mesolimbic dopaminergic neurons in the brain, and this neurotransmitter system has been considered as essential in drug reinforcement and self-administration behavior. Nicotine, however, affects other neuronal systems, and in particular changes the endogenous opioids in the brain. In preliminary studies, it was found that an acute injection of nicotine to mice, increased the striatal levels of met-enkephalin and dynorphin, as well as their mRNAs. Furthermore, during withdrawal from a chronic treatment with nicotine, the changes in the levels of the opioids and their mRNAs were associated with changes in the levels of mRNAs for their receptors. These data suggest that nicotine interferes with endogenous opioids, and that its addictive properties may be indirect and related to this interaction. Nicotine may be modulating the expression of the brain opioids through an induction of transcription factors such as c-fos and c-jun which can interact with the AP1 site of the opioid genes. In fact, acute nicotine induced an increase in c-fos and c-jun mRNAs and an enhancement of AP1 binding detected by gel shift assay in striatum. The goal of this project is to investigate a role for the opioids in nicotine addiction and abstinence. The aim of this proposal is to localize the areas where the nicotine-induced changes of opioids occurred in the brain, and to characterize pharmacologically the effects of nicotine on these opioids systems, after acute administration and during withdrawal. The levels and mechanisms of this interaction will also be investigated by studying the effects of nicotine on opioid synthesis and release, and the rates of transcription of the opioid genes. A better understanding of the mechanisms of nicotine addiction may facilitate the implementation of stronger prevention policies, and the development of new curative alternatives.